Essential hypertension is a major source of morbidity and mortality in the general population, and a significant percentage of hypertensive patients manifest salt-sensitive hypertension. Although the etiology of salt-sensitive hypertension is undoubtedly multifactorial, there is experimental and epidemiologic evidence linking abnormalities in the cyclooxygenase (COX)/prostaglandin system to its pathogenesis. COX-2 inhibitors, as well as non-selective non-steroidal anti-inflammatory drugs (NSAIDs), are known to elevate blood pressure (BP) and antagonize the BP-lowering effect of antihypertensive medication in many users. A COX-2 polymorphism that reduces enzymatic activity has been associated with increased risk of stroke in African Americans. Selective inhibition of COX-2 has been implicated in increased cardiovascular mortality, which appears to be multifactorial, and may involve increases in BP and salt and water retention in addition to accelerated thrombogenesis. Therefore, COX-2 activity seems to be an important mediator of salt and water homeostasis and a guard against development of salt- sensitive hypertension. The mechanism by which COX inhibition leads to development or exacerbation of hypertension has been attributed to inhibition of renal COX-2 activity, since salt loading up-regulates COX-2 expression in the renal medulla, and COX-2 inhibitors reduce urinary sodium excretion. However, there continues to be controversy about the cellular origins and regulation of the COX-2-derived prostaglandins that regulate salt and volume homeostasis. Our recently published and preliminary results provide a novel paradigm to be tested: that COX-2-derived prostaglandins from renal medullary interstitial cells (RMICs) and renal resident macrophages/dendritic cells work in parallel to regulate salt and water and blood pressure homeostasis and that abnormalities in either can lead to development of salt-sensitive hypertension. To test this hypothesis, we propose three specific aims: Specific Aim I Investigate the Functional and Structural Roles of COX-2 Expression in Renal Medullary Interstitial Cells (RMICs) Specific Aim II Determine Mechanisms by Which Inhibition of Renal Macrophage/Dendritic Cell COX-2 Expression or Activity Can Potentiate Salt-Sensitive Hypertension Specific Aim III Determine the Potential Physiologic Role of Renal Macrophages/Dendritic Cells in Response to Chronic Volume Depletion !